Specific drugs with a high risk of clinically important interactions

The following is an edited extract from The ESC Handbook on Cardiovascular Pharmacotherapy. To find out how to access this title online, please click here. Alternatively, you can buy print copies online here.

Interactions affecting antiarrhythmic drugs

AADs are highly heterogenous but are often regarded as being high-risk drugs because of the risk of toxicity leading to severe ventricular arrhythmia. Both PK and PD interactions differ among these drugs. Concerning PD interactions, a major issue is the risk of QT interval prolongation, and thereby a risk of TdP, due to the combination of drugs that have the ability to prolong the QT interval. However, this risk may also arise due to PK interactions or due to side effects of other drugs causing metabolic disturbances. There is some consensus on not to combine drugs with a high risk of causing prolongation of the QT interval and to be cautious when combining drugs with a moderate risk. Some of the most commonly used AADs are discussed in more detail in the following sections.

Beta-adrenoceptor antagonists

At present, β‎-adrenoceptor antagonists are generally considered as almost ideal AADs because of their broad antiarrhythmic effect and good safety profile. PK interactions vary among these drugs, with the most lipophilic β‎-adrenoceptor antagonists primarily metabolized by CYP2D6. Hence, drugs that inhibit this enzyme, e.g. propafenone, the antifungal terbinafine when used systemically, antidepressants such as fluoxetine, paroxetine (strong inhibitors), duloxetine, and sertraline, and cimetidine (moderate inhibitors), increase the plasma concentration of these β‎-adrenoceptor antagonists. Verapamil inhibits the hepatic breakdown of lipophilic β‎-adrenoceptor antagonists, increasing their plasma concentration. The most water-soluble β‎-adrenoceptor antagonists (e.g. atenolol and sotalol) are mainly excreted by the kidneys and are therefore rarely subjected to DDIs. β‎-adrenoceptor antagonists have a broad therapeutic index, and most patients tolerate a rise in their plasma concentrations, with the exception of HF patients in whom slow and careful titration may be warranted. Concerning PD interactions, there is a risk of additive cardiac depressant effects, such as hypotension and bradycardia, when used in combination with other drugs with similar side effects. β‎-adrenoceptor antagonists inhibit the competitive binding of catecholamines to β‎-adrenoceptors, thereby potentially decreasing the effect of these drugs, but with some differences between the drugs. β‎1-selective drugs (e.g. atenolol and metoprolol) selectively block receptors in cardiac tissue, but at high dosages, they also affect β‎2 receptors. Non-selective drugs block receptors (β‎2) in the lung and blood vessels (e.g. propranolol and carvedilol—carvedilol also block α‎1 receptors).

Calcium channel antagonists

Verapamil and diltiazem are mainly metabolized by CYP3A4. Thus, drugs that inhibit CYP3A4, e.g. erythromycin, clarithromycin, most azole antifungals, and some antiviral agents, increase the plasma concentration of these calcium channel antagonists, and inducers, such as rifampicin, will decrease their plasma concentration (see Table 7.1.2). The main issue concerning interactions with verapamil is its ability to inhibit CYP3A4 and P-gp. Verapamil may nearly double plasma digoxin levels2 and increase the levels of dabigatran, quinidine, ciclosporin, simvastatin, atorvastatin, and lovastatin. Diltiazem interacts with the same drugs, but to a lesser extent. Verapamil and diltiazem inhibit the AVN, causing PD interactions with other drugs that also inhibit the AVN, e.g. β‎-adrenoceptor antagonists, digoxin, and amiodarone. Verapamil cause arteriolar dilatation and exerts a direct negative inotropic effect on the heart. The negative inotropic effect of combining verapamil and disopyramide is considerable.

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